Alpha-amino-alpha, alpha-diphenylacetic acid derivatives and method of preparing same



Patented June 16, 1953 a-AMiNO-ma-DIPHENYLACETIC ACID DE- RIVATIVES AND METHOD OF PREPAR- ING SAME Robert Duschinsky, Essex Fells, N: 1., assignor to Hofimann-La Roche Inc., Nutley, N. J., a corporation of New Jersey No Drawing. Application November 17,1949, SerialNo. 128,006

This invention in its broader aspects relates to a new method for preparing generally a-aminoc,a-diphenylacetamides, a-amino-a,a-diphenylacetic acid esters, and a,amino-a,a-diphenylthioe acetic acid esters. Another, more particular,

aspect of. the invention embraces as new com-,

pounds the lower alkyl esters of a.-amlDO,-a,a-

diphenylacetic acid and the corresponding esters of a-amino-a,a-diphenylthioacetic acid. The invention further encompasses as he compounds the tertiaryaminoalkyl esters of a-amino-a,a-diphenylacetic acid and the corresponding esters of c-amino-a,a-diphenylthioacet1c 18 Claims. (01. 260-2943) acid, and the salts thereof, which in the form of their free basescan be represented by the followin formula: Ph2C(NI-I2) --CO-XC1-IzRN(R1) (R2) where Ph stands for a phenyl radical, X for oxygen or sulfur, R. for a lower alkylene radical,

and R1 and R2 are members of the class con-' sisting of lower alkyl radicals and further members where R1 and R2 taken with N form a heterocyclic radical, as piperidino, morpholino, an pyrrolidino radicals.

Compounds of the instant invention are of interest for their medicinal properties, for ex ample, as analgesics, hypnotics, anticonvulsants as, for example, ammonia, a primary amine, as

methylainine, ethylamine, z-amino-ethanol, pro

pylamine, aniline, benzylamine, benzh-ydrylamine; The reaction is carried out vpref-: erably by heating the reagents in the presence of and the like.

01s and tertiaryaminoalkanethiols employed can i be represented by the following formula;

HX-CI-I2RN (R1) (R2) wherein X, R, R1 and R2 have the same-meaning 'melts at 166-167" C.

The following examples will serve to illustrate 2 r as hereinabove assigned thereto. The reaction is readily carried out by heating the reagents in the presence of a suitable solvent or by fusing the reagents together, preferably in the presence of an hydrogen halide, such as hydrogen chloride or hydrogen bromide, whereby the hydrohalides of the esters are directly obtained. The hydrohalide salts can be readily converted into the free bases with an alkaline agent as, for example, sodium hydroxide, sodium carbonate, or ammonia in the usual manner.

The 4,4-diphenyl-2,5-oxazolidinedione is a new" compound, and is claimed in my application Serial No. 128,005, filed of even date herewith and now United States Patent No. 2,578,293,

It can be prepared issued December-11, 1951. as described therein by reacting a-aminoidiphenylacetic acid withiethyl chloroformate to form a-carbethoxyamino-a,a-diphenylacetic acid, and cyclizing the latter compound with thionyl chloride. 2,5-oxazolidinedione can be prepared as follows. To a solution 'of 41.7 grams of a-amino-a,a-di phenylacetic acid in 200 cc. of 1 N sodium hydroxide there were added in portions with stirring l N sodium hydroxide and ethyl chloroformate until a total of 615 cc. of sodium hydroxide and 56.6 rams of ethyl chloroformate had been used. 400 cc. of ether were then added and the mixture was acidified with 80 cc. of 5 N hydrochloric acid and shaken. The ether layer was separated, the aqueous layer was extracted with 200 cc. of ether, and the combined ether layers were dried over sodium sulfate, and evaporated. The resulting oily residue upon cooling yielded crude crystalline a-carbethoxyamino a,a. diphenylacetic acid, a sample of which upon recrystallization from benzene-petroleum ether, melted at 152-153 C. The crude a-carbethoxyamino-a,a-diphenylacetic acid was mixed with cc, of thionyl chloride and heated for 30 minutes at C. by which time gas evolution had stopped and crystals had begun toseparate. Excess thionyl chloride was evaporated and the residue was crystallized by mixing with cc. of benzene and gradual addition of 150 cc. of petroleum ether. The mother liquor yielded a second crop of crystals upon evaporation and addition'of petroleum ether. The 4,4- diphenyl 2,5 oxazolidinedione thus the invention.

Example 1 cc. of 28 per cent aqueous ammonia were More specifically, the 4,4-diphenyl-' obtained A solution of 8.5 grams of a-amino-a,a-di-- phenylacetamide in 25 cc. of ethanol was mixed with 5 cc. of 9 N alcoholic hydrochloric acid. Upon addition of cc. of ether, a-amino-a,a-diphenylacetamide hydrochloride crystallized,

M. P. 258 C. The salt is readily soluble in water.

Example 2 A mixture of 5 grams of 4,4-diphenyl-2,5-oxazolidinedione and 50 cc. of 25 per cent aqueous methylamine was heated with stirring on a water bath. After 25 minutes the temperature had reached 75 C. and the gas evolution had stopped. Upon cooling, a-amino-a,a-diphenyl-N-methylacetamide crystallized. The crystals were filtered, washed with water, then with 2 cc. of a mixture of equal volumes of ethanol and ether, and finally with 10 cc. of ether. The purified a-amino-a,a-diphenyl-N-methylacetamide melted at 133-134 C.

For the conversion into the hydrochloride the a-amino-a,a-diphenyl-N-methylacetamide was dissolved in cc. of ethanol by heating at 60 C. The solution was acidified with 4 cc. of 5.9 N a1- coholic hydrochloric acid, and upon addition of ether, the hydrochloride of a-amino-a,a-diphenyl-N-methylacetamide crystallized, M. P. 236-239" C. The substance was dried in vacuo at 120 C. in order to remove ethanol of crystallization.

Example 3 A mixture of 1 gram of 4,4-diphenyl-2,5-oxazolidinedione and 1 cc. of 2-aminoethanol was heated gradually in a nitrogen atmosphere up to 250 C. After hour, evolution of the carbon dioxide which formed during the reaction had stopped. The excess of the 2-aminoethanol was then evaporated in vacuo at 250 C. The

remaining thick oil, yielded when taken up with.

alcoholic hydrochloric acid followed by addition of ether, crystals of a-amino-a,a-diphenyl-N- (Z-hydroxyethyl)acetamide hydrochloride melting at 171-173 C., which after recrystallization from ethanol-ether melted at l'77-1'79 C.

Example 4 A solution of 2.5 grams of 4,4-diphenyl-2,5- oxazolidinedione in 10 cc. of dioxane was mixed with 1.8 cc. of aniline and then refluxed for 10 minutes. It was then evaporated on the steam bath and heated thereon for 2 hours. The solid residue obtained was recrystallized from 25 cc. of ethanol, yielding a-amino-a,a,N-triphenylacetamide, M. P. 145-146 C. By treating the amide with hydrochloric acid, the water soluble hydrochloride was obtained.

Example 5 A mixture of 0.25 gram of 4,4-diphenyl-2,5- oxazolidinedione and 0.43 gram of benzylamine was heated'to 150-160 C. for 20 minutes. The resulting oil was crystallized from aqueous ethanol. The crude amide was transformed into the hydrochloride by adding alcoholic hydrochloric acid and ether. The resulting a-amino-a,a-diphenyl-N-benzylacetamide hydrochloride melt- Ed at 230 C.

Example 6 A mixture of 1 gram of 4,4-diphenyl-2,5-oxazolidinedione and 0.69 cc. of benzhydrylamine was heated at 160-175 C. for 40 minutes by which time the carbon dioxide evolution had stopped. The reaction mixture was dissolved in l0 cc. of dioxane. Upon addition of 20 cc. of petroleum .ether, crystals of a-amino-a,a-diphenyl-N-benzhydrylacetamide, melting at 163-l64 C, were obtained. After recrystallization from ethanol the compound melted at 165 C.

Example 7 A solution of 6 grams of 4,4-diphenyl-2,5-oxazolidinedione in 60 cc. of 5.9 N ethanolic hydrochloric acid was refluxed for A. of an hour. Considerable evolution of carbon dioxide occurred. Introduction of hydrogen chloride gas into the cooled mixture and refluxing produced only a slight additional evolution of carbon dioxide. The reaction mixture was then evaporated to dryness giving a crystalline mass which was treated with 20 cc. of acetone and 20 cc. of ether. The ethyl a-amino-a,a-diphenylacetate hydrochloride thus obtained melted at about 200 C. It could be recrystallized from dioxane.

For the preparation of the base 11.7 grams of the hydrochloride was shaken with cc. of 1 N sodium carbonate and 50 cc. of ether. ous layer was extracted with 25 cc. of ether. The combined ether layers were dried over sodium sulfate. of the extract was crystallized from petroleum 35 ether yielding thin prisms of ethyl a-amino-a,a-

Example 8 A mixture of 1 gram of 4,4-diphenyl-2,5-oxazolidinedione and 0.36 gram of 2-dimethylaminoethanol was heated for 20 minutes at 150 C. in a stream of dry hydrogen chloride gas. The melted reaction mixture was crystallized from a mixture of acetone, ethanol and ether. After recrystallization from methanol-ether the 2-dimethylaminoethyl a-amino-a,a-diphenylacetate dihydrochloride melted at 225 C. (with decomposition).

Example 9 A'mixture of 7.6 grams of 4,4-diphenyl-2,5- oxazolidinedione and '4.6 grams of Z-diethylaminoethanol hydrochloride was fused in a stream of hydrogen chloride gas at -150" C. for one hour. The hydrogen chloride gas was swept out :by nitrogen and the residue was crystallized from- Example 10 A mixture of 5.06 grams of 4,4-diphenyl-2,5- oxazolidinedione and 4 grams of 2,2-dimethyl-3- diethylaminopropanol hydrochloride was fused 1n a stream of hydrogen chloride gas at 140 C. for 25 minutes. After displacement of the hydrogen chloride gas by nitrogen the obtained meltwas crystallized from 30 cc. acetone. The product was recrystallized by dissolving it in 20 cc. of methanol and addition of 30 cc. of acetone and 30 cc. of ether, the resulting 2,2-dimethyl-3-diethylaminopropyl The aque'-.

The residue obtained after evaporation.

a-amino- ,a-dipheny1acetate dihydrochloride melted with decomposition at 230 C.

Example 11 A mixture of 1 gram of 4, i-diphenyl-2,5-oxazolidinedione and 0.52 gram of i-piperidineethanol wa fused in a stream of hydrogen chloride gas at 155 C. for one hour. After displacement of the hydrogen chloride gas by nitrogen,

the solid residue was taken up and washed with acetone. After recrystallization from 30 cc. of methanol and 60 cc. of ether the 2-(l-piperidylethyl) a-amino-a,a-diphenylacetate dihydrochloride melted with decomposition at 244 C.

Example 12 A mixture of 7.6 grams of 4,4-diphenyl-2,5 oxazolidinedione and 5.09 grams of diethylaminoethanethiol hydrochloride was fused in an oil bath of 14.0-150 C. for 25 minutes while a stream of hydrogen chloride gas was passed through the melt. After displacement of the hydrogen chloride gas by nitrogen, acetone and ether were added to the melt whereupon 2-diethylaminoethyl a-amino-aa-diphenylthiolacetate dihydrochloride crystallized. After recrystallization from methanol-ether the compound melted at 230 C. with decomposition.

I claim: A

1. The process which comprises reacting by heating 4,4-diphenyl-2,5-oxazolidinedione with a member of the group consisting of a lower alkanol, a lower alkanethiol, a lower tertiaryaminoalkanol, and a lower tertiaryaminoalkanethiol in the presence of an hydrogen halide to form the corresponding a-amino-a,a-diphenylacetic acid ester hydrohalides and a-aminoa -diphen- 6 bers of the class consisting of a lower alkyl radical and further members where R1 and R2 taken together with N form a saturated heterocyclic radical.

ylthioacetic acid ester hydrohalides, said tertiwherein X stands for a member of the group consisting of oxygen and sulfur, R for a lower alkylene radical, and R1 and R2 are members of the class consisting of lower alkyl radicals and further members where R1 and R2 taken with N form a saturated heterocyclic radical.

2. The process as in claim 1 wherein the hydrogen halide is hydrogen chloride.

3. The process according to claim 1 wherein the oxazolidinedione is reacted with a lower tertiaryaminoalkanol.

4. The process according to claim 1 wherein the oxazolidinedione is reacted with a lower tertiaryaminoalkanethiol.

5. A compound of the group consisting of a tertiaryaminoalkyl ester and the salts thereof which in the form of the free base can be represented by the following formula:

wherein Ph is a phenyl radical, X is a member of 6. A compound according to claim 5 wherein the formula X stands for oxygen and N taken with R1 and R2 is a heterocyclic radical.

7. A compound according to claim 5 wherein the formula X stands for oxygen and R1 and R2 stand for lower alkyl radicals.

8. A compound according to claim 5 wherein the formula X, stands for sulfur and R1 and R2 stand'for lower alkyl radical-s.

9. A process which comprises reacting by heating 4,4-diphenyl-2,5-oxazolidinedione with 2 -dimethylaminoethanol in' the presence of hydrogen chloride so as to produce 2-dimethylaminoethyl a-amino-a,a-diphenylacetate 'dihydrochloride.

10. A process which comprises reacting by heating 4,4-diphenyl-2,5-oxazolidinedione with 2-diethylaminoethano1 hydrochloride in the pres- V phenyl-2,5-oxazolidlnedione with Z-diethylaminoethanethiol .hydrochloride in the presencev of hydrogen chloride so as to produce 2-diethylami-' noethyl a-amino-a,a-diphenylthiolacetate dihydrochloride. I

14. 2-dimethylaminoethyl a-amin0-.a,a-diphen ylacetate dihydrochloride.

15. Z-diethylaminoethyl a-amino-a,a-diphenylacetate dihydrochloride.

16. 2,2-dimethyl-3-diethylaminopropyl a-amino-a,adiphenylacetate dihydrochloride. I

17. 2-(1-piperidylethyl) a-amino-a,a-diphenylacetate dihydrochloride. p

18. 2-diethylaminoethyl a-amino-ma-diphenylthiolacetate dihydrochloride.

. ROBERT DUSCI-IINSKY.

References Cited in the file of this patent FOREIGN PATENTS Country Date Denmark Feb. 3, 1947 OTHER REFERENCES Number Leuchs, Beilstein (Handbuch, 4th ed.), vol. 7

Leuchs et al., Beilstein (l-Iandbuch, 4th ed.),

- vol. 27, p. 246 (-1937).

Biltz, Liebigs Ann., vol. 391, pp. 215-230 (1912). 

1. THE PROCESS WHICH COMPRISES REACTING BY HEATING 4,4-DIPHENYL-2,5-OXAZOLIDINEDIONE WITH A MEMBER OF THE GROUP CONSISTING OF A LOWER ALKANOL, A LOWER ALKANETHIOL, A LOWER TERTIARYAMINOALKANOL, AND A LOWER TERTIARYAMINOALKANETHIOL IN THE PRESENCE OF AN HYDROGEN HALIDE TO FORM THE CORRESPONDING A - AMINO-A,A-DIPHENYLACETIC ACID ESTER HYDROHALIDES AND A-AMINO-A,A-DIPHENYLTHIOACETIC ACID ESTER HYDROHALIDES, SAID TERTIARYAMINOALKANOL AND TERTIARYAMINOALKANETHIOL BEING REPRESENTED BY THE FOLLOWING FORMULA:
 5. A COMPOUND OF THE GROUP CONSISTING OF A TETRIARYAMINOALKYL ESTER AND THE SALTS THEREOF WHICH IN THE FORM OF THE FREE BASE CAN BE REPRESENTED BY THE FOLLOWING FORMULA: 